Elite suppressors are HIV-1 infected patients who maintain viral loads of <50 copies/ml without antiretroviral therapy. We have recently shown for the first time that replication competent virus can be isolated from some of these individuals suggesting that immunologic control of replication competent HIV-1 is possible. The mechanism of control has yet to be defined in these patients, but we have shown that superior humoral immunity is not the cause of control in many ES and neither is an intrinsic resistance to HIV-1 infection. We have shown that provirus from these patients also do not have higher levels of APOBEC 3G/F mediated hypermutation. Taken together it appears that superior HIV-specific cellular immunity plays a key role in the control of viremia in elite suppressors. While the mechanism of CD8+ T cell mediated control is unknown, it has been shown that elite suppressors and patients with progressive disease have similar frequencies of HIV-specific CTL. However, it has recently been shown that unstimulated CD8+ T cells from elite suppressors, but not patients with progressive disease, are able to control the replication of a laboratory strain of HIV-1 in autologous CD4+ T cells. This is a physiological model since the CD8+ T cells are not activated prior to being used in the assay and the CD4+ T cells process and present HIV antigens (as opposed to peptides being added to the cells in culture). The objective of this proposal is to determine the mechanisms by which this CD8+ T cell mediated control of this replication competent virus is achieved. We plan to identify the major subset of CD8+ T cells involved in this control. We will also distinguish between cytotoxic killing of target cells and non-cytotoxic mediated suppression of viral replication. We will define the kinetics of the CD8+ T cell mediated control and determine whether Nef mediated down regulation of MHC class I proteins is a mechanism used by the virus to evade this control of viral replication. This work will be important for the development of vaccines that can be used to improve the HIV specific immune responses in HIV-1 infected individuals. This may allow some patients to control the virus without antiretroviral therapy for prolonged periods of time. PUBLIC HEALTH RELEVANCE: Most patients infected with HIV-1 will develop a drop in their CD4 counts and frank AIDS as the virus replicates and destroys the immune system. A unique group of untreated HIV-1-infected patients, termed Elite Suppressors (ES) are able to completely control the virus and do not develop AIDS (1-3). This project plans to determine how CD8+ T cells from ES control the virus;the results may be applicable to the development of an effective HIV-1 vaccine.